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Tag: Pharmacology

  • New research identifies potential drug target to prevent kidney failure

    New research identifies potential drug target to prevent kidney failure

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    A new study found that retinoic acid receptors (RARa) in the proximal tubules of the kidney play a crucial role in limiting the damaging effects of kidney injury that often lead to kidney failure. Researchers from Weill Cornell Medicine have developed a preclinical model that showed a condition like chronic kidney disease develops when RARa in proximal tubules stop working.

    Currently, there are few drugs on the market, so patients with prolonged, untreated kidney disease must undergo dialysis or kidney replacement. The paper, published in PNAS on Feb. 8, suggests drugs that can activate RARa in the kidney could counteract fibrosis—the buildup of scar tissue that results from inflammation caused by diabetes, autoimmune diseases or viral infections like COVID-19—to treat kidney disease.

    Our kidneys filter blood to remove waste, which is excreted in urine. Proximal tubules are an important part of this process and return the substances needed by the body back into the blood. The RARa help maintain the health of proximal tubules and keep the kidneys working.

    When RARa is knocked out in the proximal tubules of their mouse model, the researchers discovered that within three days mitochondria that produce energy in cells become distressed and cells start dying. After three months, they observed that epithelial cells in the proximal tubule secreted growth factors that led to fibrosis and decreased levels of retinoic acid, which normally binds to the RARa.

    Stopping progressive renal fibrosis, a hallmark of late-stage chronic kidney disease, would be one way to prevent kidney failure. The researchers hope to use their novel mouse model to identify drugs that activate RARa to slow or reverse fibrosis and to potentially return kidneys to a healthy state.

    Source:

    Journal reference:

    DiKun, K. M., et al. (2024) Retinoic acid receptor α activity in proximal tubules prevents kidney injury and fibrosis. Proceedings of the National Academy of Sciences of the United States of America. doi.org/10.1073/pnas.2311803121.

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  • Schisanhenol suppresses cytokine storm and acute lung injury in mice

    Schisanhenol suppresses cytokine storm and acute lung injury in mice

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    Background and objectives

    Cytokine storm (CS) is an acute systemic inflammatory response with limited effective interventions up to now. The treatment experience of the COVID-19 pandemic suggests great potential in the intervention of CS by herbal medicine. This study aimed to investigate whether Schisanhenol (SSH), an active component of the Chinese herbal medicine Schisandra chinensis, has the potential to interfere with CS.

    Methods

    The effect of SSH on nuclear factor-kappa B (NF-κB) signaling pathway activity was observed with THP-1/NF-κB cells. THP-1 and abdominal macrophages were used as cell models to observe the effect of SSH on inflammatory responses. The lipopolysaccharide-induced acute inflammatory response in mice was used to observe the effect of SSH on systemic inflammatory response and induced acute lung injury. The potential biological mechanism of SSH against inflammatory storm was explored by network pharmacology and molecular docking methods.

    Results

    SSH significantly inhibited NF-κB pathway activity and suppressed macrophage and systemic inflammatory responses in mice. SSH also effectively alleviated lipopolysaccharide-induced acute lung injury. The network pharmacology results showed that estimated glomerular filtration rate, matrix metalloproteinase 9, proto-oncogene tyrosine-protein kinase Src, and mammalian target of rapamycin are potential key target proteins of SSH.

    Conclusions

    The findings of this study demonstrate that SSH inhibited the macrophage inflammatory response and cytokine production at both the systemic and local levels in mice. Additionally, SSH effectively mitigated acute lung injury resulting from CS. Furthermore, network pharmacological analysis revealed that SSH has the ability to suppress inflammatory response through multiple mechanisms.

    Source:

    Journal reference:

    Qi, W., et al. (2023). Schisanhenol: A Potential Drug for the Treatment of Cytokine Storm. Exploratory Research and Hypothesis in Medicine. doi.org/10.14218/ERHM.2023.00054.

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  • Research validates concurrent use of HIV medications and gender-affirming hormone therapy

    Research validates concurrent use of HIV medications and gender-affirming hormone therapy

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    New research definitively shows that HIV antiretrovirals can be taken together with gender-affirming hormone therapy without changing how well either drug works. The study findings can help healthcare providers address potential patient concerns that one drug will counteract the other.

    This study is the first head-to-head pharmacokinetic analysis of two common HIV medications and long-term feminizing hormone therapy use. This research should help doctors reassure patients that it’s safe and important to continue HIV medications alongside their hormone regimen.”


    Walter Kraft, MD, Director of the Division of Clinical Pharmacology at the Sidney Kimmel Medical College at Thomas Jefferson University

    The study was published in the journal, Clinical and Translational Science.

    Transgender women are at a 50 times greater risk of HIV infection than the general public, and stopping HIV medication can have long-term consequences, including disease progression to AIDS.

    The study enrolled eight transgender women who were taking gender-affirming hormone therapy and who were HIV negative. As part of the cross-over study, half of the women were asked to take one of three treatments – one after the other: first HIV therapy, then hormone therapy and then finally, a combination of the two. There was a 14-day “wash-out” period between each therapy when participants took no therapy. The researchers took blood and urine samples regularly to test for drug and hormone concentrations during and after treatment.

    To ensure the order of treatments didn’t affect the result, the other half of the women in the study had the treatment in the opposite order, starting with the combination hormone plus HIV therapy, followed by hormone therapy alone, and then HIV medication alone. 

    Although the number of patients wasn’t large, the amount of data collected on each participant was comprehensive. In addition, the use of a cross-over study design – where each participant takes each of the therapy combinations and essentially serves as her own control – provided enough statistical power to confirm the scientific validity of the findings. The duration and intensity also speaks to the personal sacrifice that each participant made in order to take part in the study.

    “We asked women who were HIV negative to participate because it wouldn’t be ethical to ask those who are HIV positive to stop taking HIV medication,” says Dr. Kraft. “We realized that it was a big ask for transgender women to halt their gender-affirming hormone therapy for the sake of science. The ones who did, understood how valuable this information could be for their community. It’s part of why this study is so important.”

    The study revealed that it is safe for patients to use HIV antiretrovirals medications together with gender-affirming hormone medications without losing potency of either drug. In fact, estrogen and testosterone levels were basically unchanged when participants also took HIV medications. “The hormone concentration in the blood was close enough that you wouldn’t have to change hormone dosing at all,” said first author Kevin Lam, PharmD. 

    “This study is so important for the trans community,” says Dr. Lam. “There’s a big risk with scaling back or stopping HIV medication. The virus can develop resistance to the medications, making them ineffective at keeping the virus in check.”

    “We hope that this study will help reassure the trans community living with HIV that it’s safe and crucial to continue taking their antiretrovirals to control HIV infection.”

    This study was conceived, written and conducted by Thomas Jefferson University employees. Funding was supported by an Investigator Studies Program grant provided by Merck & Co., Inc. [MISP59198]. K.L. and E.L. were supported by the National Institutes of Health institutional training grant [T32GM008562].

    Source:

    Thomas Jefferson University

    Journal reference:

    Lam, K., et al. (2024) Bidirectional pharmacokinetics of doravirine, tenofovir, and feminizing hormones in transgender women (IDentify): A randomized crossover trial. Clinical and Translational Science. doi.org/10.1111/cts.13721.

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  • Interdisciplinary project aims to decode human kinome in brain function and disease

    Interdisciplinary project aims to decode human kinome in brain function and disease

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    The Chan Zuckerberg Initiative (CZI) announced four multi-year Exploratory Cell Networks grants for researchers exploring the frontiers of genomics, cell biology, and synthetic biology by developing new measurement technologies. The projects will be bringing together regional labs in California, the Mid-Atlantic, and the Research Triangle.

    Klaus Hahn, PhD, the Ronald G. Thurman Distinguished Professor of Pharmacology and member of the UNC Lineberger Comprehensive Cancer Center, will be co-leading a project titled, “Research Triangle: Revealing the Hidden Topologies of the Human Kinome” with Scott Soderling, PhD, a cell biologist at Duke University and Albert Keung, PhD, a chemical and biomolecular engineer at North Carolina State University.

    Each of the three institutions will receive a million dollars, awarded over three years, with potential extension into future years. The three investigators share leadership of this effort, which is made possible by interlocking the diverse technologies of their labs.

    The Triangle groups will focus on the “kinome”, a set of over 500 proteins that function as “molecular switches” crucial to nervous system function, neurological disease, and a range of non-neurological disorders. p38 kinases, for example, respond to stress stimuli and are involved in cognitive and emotional functions, including anxiety, neurodegeneration, and high-level decision making.

    Much work has led to an understanding of specific kinases and how they function. Because kinases work together as members of large circuits, it is also important for researchers to see how they affect one another and operate as a whole.

    This is the goal of the new project -; which combines the Keung lab’s ability to map out the connections and interactions among many kinases, the Soderling lab’s ability to understand how these connections are placed and act within the brain, and the Hahn lab’s ability to see and control kinase activities in real time to understand how transient activation events regulate the circuitry.

    The researchers are developing new tools to correlate information about these different aspects of kinase behavior, and to study kinases at scale inside the neural system of a living organism (in vivo). The Keung lab is creating new instruments and molecular screening approaches to provide precise, quantitative information about which kinases interact and how fast and tight these interactions are.

    The Soderling group will probe kinase activities in living brains, examining which of these potential interactions occur during specific behaviors. The Hahn lab will develop capabilities to stop or start kinases in live brains, and to visualize their activation in real time. This information will be brought together by Soderling at Duke using an integrated computational model of the human kinome.

    This multi-faceted research project, which includes tool development, experimental application and modeling, has implications for tackling many other types of proteins and other high-dimensional cell biological problems, spanning multiple human diseases. The ultimate goal of this project is to identify new therapeutic targets in the brain, and to generate novel diagnostic tools that report and interpret dynamic changes in the human kinome.

    Source:

     University of North Carolina Health Care

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  • Delta opioid receptor agonist reduces anxiety-like behavior in mice

    Delta opioid receptor agonist reduces anxiety-like behavior in mice

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    Anxiety-related disorders can have a profound impact on the mental health and quality of life of affected individuals. Understanding the neural circuits and molecular mechanisms that trigger anxiety can aid in the development of effective targeted pharmacological treatments. Delta opioid receptors (DOP), which localize in the regions of the brain associated with emotional regulation, play a key role in the development of anxiety. Several studies have demonstrated the therapeutic effects of DOP agonists (synthetic compounds which selectively bind to DOPs and mimic the effect of the natural binding compound) in a wide range of behavioral disorders. One such selective DOP agonist-;KNT-127-;has been shown to exert ‘anxiolytic’ or anxiety-reducing effects in animal models, with minimal side effects. However, its mechanism of action is not clearly understood, thereby limiting its widespread clinical application.

    To bridge this gap, Professor Akiyoshi Saitoh, along with Ms. Ayako Kawaminami and team from the Tokyo University of Science, Japan, conducted a series of experiments and behavioral studies in mice. Explaining the rationale behind their work, Prof. Saitoh says, “There are currently no therapeutic drugs mediated by delta opioid receptors (DOPs). DOPs likely exert anti-depressant and anti-anxiety effects through a mechanism of action different from that of existing psychotropic drugs. DOP agonists may, therefore, be useful for treatment-resistant and intractable mental illnesses which do not respond to existing treatments.”  Their study was published on 29 December 2024, in Neuropsychopharmacology Reports,

    The neuronal network projecting from the ‘prelimbic cortex’ (PL) of the brain to the ‘basolateral nucleus of the amygdala’ (BLA) region, has been implicated in the development of depression and anxiety-like symptoms. The research team has previously shown that KNT-127 inhibits the release of glutamate (a key neurotransmitter) in the PL region. Based on this, they hypothesized that DOP activation by KNT-127 suppresses glutamatergic transmission and attenuates PL-BLA-mediated anxiety-like behavior. To test this hypothesis, they developed an ‘optogenetic’ mouse model wherein they implanted a light-responsive chip in the PL-BLA region of mice and activated the neural circuit using light stimulation. Further, they went on to assess the role of PL-BLA activation on innate and conditioned anxiety-like behavior.

    They used the elevated-plus maze (EPM) test, which consists of two open arms and two closed arms on opposite sides of a central open field, to assess behavioral anxiety in the mice. Notably, mice with PL-BLA activation spent lesser time in the central region and open arms of the maze, compared to controls, which was consistent with innate anxiety-like behavior. Next, the researchers assessed conditioned fear response of the animals by exposing them to foot shocks and placing them in the same shock chamber the following day without re-exposing them to current. They recorded the freezing response of the animals which reflects fear. Notably, animals with PL-BLA activation and controls exhibited similar behavior, suggesting that distinct neural pathways control innate anxiety-like behavior and conditioned fear response.

    Finally, they examined the effects or KNT-127 treatment on anxiety-like behavior of mice using the EPM test. Remarkably, animals treated with KNT-127 exhibited an increase in the percentage time spent in the open arms and central field of the maze, compared to controls. These findings suggest that KNT-27 reduces anxiety-like behavior induced by the specific activation of the PL-BLA pathway.

    Overall, the study reveals the role of the PL-BLA neuronal axis in the regulation of innate anxiety, and its potential function in DOP-mediated anxiolytic effects. Further studies are needed to understand the precise underlying molecular and neuronal mechanisms, for the development of novel therapies targeting DOP in the PL-BLA pathway.

    Highlighting the long-term clinical applications of their work, Prof. Saitoh remarks, “The brain neural circuits focused on in this study are conserved in humans, and research on human brain imaging has revealed that the PL-BLA region is overactive in patients with depression and anxiety disorders. We are optimistic that suppressing overactivity in this brain region using DOP-targeted therapies can exert significant anxiolytic effects in humans.”

    Source:

    Tokyo University of Science

    Journal reference:

    Saitoh, A., et al. (2018). The delta opioid receptor agonist KNT-127 in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice. Behavioural Brain Research. doi.org/10.1016/j.bbr.2017.08.041.

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